[Atypical antipsychotics and sexual dysfunction: five case-reports associated with risperidone].
Sexual and reproductive function side effects of atypical antipsychotics are frequent, often underestimated and badly tolerated. They contribute to the 50% rate of non-compliance reported for treated patients. Prevalence of sexual dysfunction associated with atypical antipsychotic treatment is high, varying from 18 to 96%. Atypical antipsychotics aren't, as a group, much better than typical antipsychotics, and among them, risperidone seems to induce more and quetiapine less sexual dysfunction. Most atypicals are non-selective, and have actions on multiple central and peripheral receptors. Among these, dopaminergic blockade could have a direct - altering motivation (desire) and reward (orgasm) - and an indirect negative influence on sexuality. Actually, the secondary hyperprolactinemia induced by some antipsychotics (typical antipsychotics, risperidone and amisulpiride), is dose-dependent, more pronounced for female patients, and may have a detrimental effect on sexual function. It also may result in hypogonadism, particularly for female patients. The long-term consequences of this secondary hypogonadism are subject to debate but potentially severe. Furthermore, the blocking and/or modulating actions of atypical antipsychotics on adrenaline, serotonine, histamine or acetyl-choline receptors all have the potential to contribute to secondary sexual problems. The pharmacological profile of risperidone, characterized by a strong affinity for D2 and alpha1 receptors, correlates with his tendency to significantly elevate prolactin levels and to produce ejaculatory disturbances. FIVE CASE-REPORTS: We describe five case-reports of sexual or hormonal disturbances associated with risperidone treatment: two cases of ejaculatory disturbance, one case of galactorrhea and two cases of amenorrhea. Alberto and David are two young male schizophrenic patients, treated with risperidone, and complaining of a total absence of ejaculation despite a preserved orgasm. Many recent case-reports describe the occurrence of retrograde ejaculation associated with risperidone but the exact prevalence is unknown. Retrograde ejaculation is thought to be related to the strong adrenolytic activity of risperidone. Alberto refused his medication because the ejaculatory dysfunction was unbearable for him. A switch to haloperidol depot was eventually well tolerated, without any sexual complaints. His case emphasizes the importance of sexual function for self-esteem and how this may amplify the intolerance to side-effects. David is on depot-risperidone in a setting of a legally forced treatment. Though he - reluctantly - accepts his medication, this side effect exacerbates his pre-existing delusions, strongly focused on sexual themes. His case illustrates how intolerance to sexual side-effects may be amplified by nature of delusions. Mireille is a 58 year old psychotic female patient, whose 2 mg risperidone treatment produced a unilateral galactorrhea. This sign became problematic because potentially visible at a time when Mireille started an activity in a sheltered occupation in town. Lowering dosage of antipsychotic allowed disappearance of the problem. Subjective responses to galactorrhea have been reported to be highly individual. Apart being a potentially visible side-effect, it may be misinterpreted as evidence of pregnancy or of a tumoral process. The cases of Ermina and Denise illustrate two contrasted situations in terms of subjective tolerability of reproductive function side-effects. Both were pre-menopausal patients with hyperprolactinemia secondary to risperidone treatment, resulting in amenorrhea. This was unbearable for Ermina. A switch to olanzapine allowed, one month later, the menses to resume. For Denise, on the other hand, the amenorrhea was a positive event, freeing her of unpleasant menses. Amenorrhea occurs in about 30% of pre-menopausal women treated with risperidone. It is a consequence of hyperprolactinemia, which, although often silent, is not devoid of potential negative consequences (ie increased risk of osteoporosis or neoplasia, worsening of psychopathology) (34). When hyperprolactinemia is symptomatic, lowering of the dose of the antipsychotic, or switching to a prolactin-sparing agent (olanzapine, quetiapine, aripiprazole and clozapine) is recommended. Before this, women with amenorrhea secondary to antipsychotic-induced hyperprolactinemia should be advised that menses may resume. Especially after long-standing amenorrhea they may assume being menopaused, hence may believe birth control measures are no longer required. The prevalence of antipsychotic-induced sexual and reproductive function side-effects is high. Clinicians should be aware of them, because they are often badly tolerated, are associated with a low satisfaction and may therefore result in low adherence with treatment. This implies for the clinician to overtly discuss with the patient of his sexuality and the potential negative impact of antipsychotic treatment on it. The recognition of these problems allows the searching together for a solution. The described cases indicate that solving the problem is often possible, provided that individual preferences and subjective impact are taken in account. Antipsychotic treatment is often prescribed for very long periods. A better knowledge of - and attention to - the associated side effects, particularly on the sexual and reproductive functions, is necessary in order to reduce some potentially negative long-term effects and to improve the adherence to treatment of our patients.


Sleep apnoea: clinical importance and facilities for investigation and treatment in the UK. Addendum to the 1993 Royal College of Physicians Sleep Apnoea report.
The potential importance of the obstructive sleep apnoea syndrome (OSA) has been recognized only in the last few years. Epidemiological studies suggest that symptomatic OSA occurs in 1-2% of middle-aged men and in approximately half that number of women. The relation of OSA to vascular disease is uncertain and the main indication for treatment is the relief of disabling sleepiness. Two recent evidence based analyses have produced diametrically opposed conclusions on the efficacy of treatment with nasal continuous positive airway pressure (CPAP). However, recent controlled studies confirm the overwhelming clinical experience of benefit. Facilities for the investigation and treatment of patients with OSA in the UK are subject to severe financial constraints and the availability of CPAP treatment lags markedly behind that in other countries for which data are available.


Population-based rates, timing, and causes of maternal deaths, stillbirths, and neonatal deaths in south Asia and sub-Saharan Africa: a multi-country prospective cohort study.
Modelled mortality estimates have been useful for health programmes in low-income and middle-income countries. However, these estimates are often based on sparse and low-quality data. We aimed to generate high quality data about the burden, timing, and causes of maternal deaths, stillbirths, and neonatal deaths in south Asia and sub-Saharan Africa. In this prospective cohort study done in 11 community-based research sites in south Asia and sub-Saharan Africa, between July, 2012, and February, 2016, we conducted population-based surveillance of women of reproductive age (15-49 years) to identify pregnancies, which were followed up to birth and 42 days post partum. We used standard operating procedures, data collection instruments, training, and standardisation to harmonise study implementation across sites. Verbal autopsies were done for deaths of all women of reproductive age, neonatal deaths, and stillbirths. Physicians used standardised methods for cause of death assignment. Site-specific rates and proportions were pooled at the regional level using a meta-analysis approach. We identified 278 186 pregnancies and 263 563 births across the study sites, with outcomes ascertained for 269 630 (96·9%) pregnancies, including 8761 (3·2%) that ended in miscarriage or abortion. Maternal mortality ratios in sub-Saharan Africa (351 per 100 000 livebirths, 95% CI 168-732) were similar to those in south Asia (336 per 100 000 livebirths, 247-458), with far greater variability within sites in sub-Saharan Africa. Stillbirth and neonatal mortality rates were approximately two times higher in sites in south Asia than in sub-Saharan Africa (stillbirths: 35·1 per 1000 births, 95% CI 28·5-43·1 vs 17·1 per 1000 births, 12·5-25·8; neonatal mortality: 43·0 per 1000 livebirths, 39·0-47·3 vs 20·1 per 1000 livebirths, 14·6-27·6). 40-45% of pregnancy-related deaths, stillbirths, and neonatal deaths occurred during labour, delivery, and the 24 h postpartum period in both regions. Obstetric haemorrhage, non-obstetric complications, hypertensive disorders of pregnancy, and pregnancy-related infections accounted for more than three-quarters of maternal deaths and stillbirths. The most common causes of neonatal deaths were perinatal asphyxia (40%, 95% CI 39-42, in south Asia; 34%, 32-36, in sub-Saharan Africa) and severe neonatal infections (35%, 34-36, in south Asia; 37%, 34-39 in sub-Saharan Africa), followed by complications of preterm birth (19%, 18-20, in south Asia; 24%, 22-26 in sub-Saharan Africa). These results will contribute to improved global estimates of rates, timing, and causes of maternal and newborn deaths and stillbirths. Our findings imply that programmes in sub-Saharan Africa and south Asia need to further intensify their efforts to reduce mortality rates, which continue to be high. The focus on improving the quality of maternal intrapartum care and immediate newborn care must be further enhanced. Efforts to address perinatal asphyxia and newborn infections, as well as preterm birth, are critical to achieving survival goals in the Sustainable Development Goals era. Bill & Melinda Gates Foundation.


Double Dissociation of Auditory Attention Span and Visual Attention in Long-Term Survivors of Childhood Cerebellar Tumor: A Deterministic Tractography Study of the Cerebellar-Frontal and the Superior Longitudinal Fasciculus Pathways.
Right cerebellar-left frontal (RC-LF) white matter integrity (WMI) has been associated with working memory. However, prior studies have employed measures of working memory that include processing speed and attention. We examined the relationships between the RC-LF WMI and processing speed, attention, and working memory to clarify the relationship of RC-LF WMI with a specific cognitive function. Right superior longitudinal fasciculus II (SLF II) WMI and visual attention were included as a negative control tract and task to demonstrate a double dissociation. Adult survivors of childhood brain tumors [n = 29, age: M = 22 years (SD = 5), 45% female] and demographically matched controls were recruited (n = 29). Tests of auditory attention span, working memory, and visual attention served as cognitive measures. Participants completed a 3-T MRI diffusion-weighted imaging scan. Fractional anisotropy (FA) and radial diffusivity (RD) served as WMI measures. Partial correlations between WMI and cognitive scores included controlling for type of treatment. A correlational double dissociation was found. RC-LF WMI was associated with auditory attention (FA: r = .42, p = .03; RD: r = -.50, p = .01) and was not associated with visual attention (FA: r = -.11, p = .59; RD: r = -.11, p = .57). SLF II FA WMI was associated with visual attention (FA: r = .44, p = .02; RD: r = -.17, p = .40) and was not associated with auditory attention (FA: r = .24, p = .22; RD: r = -.10, p = .62). The results show that RC-LF WMI is associated with auditory attention span rather than working memory per se and provides evidence for a specificity based on the correlational double dissociation.


Hepatitis A Virus in Lao People's Democratic Republic: Seroprevalence and Risk Factors.
Despite several recent reports of outbreaks of hepatitis A, little is known about the disease burden in Lao People's Democratic Republic (PDR). We conducted a cross-sectional age-stratified seroprevalence study of anti-hepatitis A virus (HAV) IgG and risk factors in a rural province (Xiengkhouang) and Vientiane capital in Lao PDR. Overall, 62% of participants were anti-HAV positive in Xiengkhouang Province compared with 45.5% in Vientiane capital. In Xiengkhouang, 23.7% of 5- to 10-year-olds were already seropositive compared with 5% in Vientiane. A dramatic increase in seroprevalence occurred between 15- to 20-year and 21- to 30-year age-groups (35.7-62.4%, Xiengkhouang, and 11.5-69.7%, Vientiane) until essentially all older adults were positive in both locations. The main risk factors for HAV antibodies were age, non-Lao-Tai ethnicity, and food-related risk factors. In conclusion, Lao children seem to be exposed very early to HAV, particularly in rural settings, and exposure continues throughout their lives, mostly without being reported. In the older birth cohorts, the high seroprevalence may largely reflect poor sanitation and exposure during childhood. In Vientiane capital, the lower seroprevalence at young ages may reflect better water sanitation since the late 1990s. A comparison with neighboring Thailand indicates that the impact of improved sanitation in Lao PDR began only two decades later. Further improvements in water sanitation, in particular in the rural districts, and better food hygiene are warranted. Our study also suggests that HAV infections are underreported. Improved reporting would provide guidance for targeted interventions to further reduce HAV infections.


Dynamic adaptation to history of trial difficulty explains the effect of congruency proportion on masked priming.
In reaction time research, there has been an increasing appreciation that response-initiation processes are sensitive to recent experience and, in particular, the difficulty of previous trials. From this perspective, the authors propose an explanation for a perplexing property of masked priming: Although primes are not consciously identified, facilitation of target processing by a related prime is magnified in a block containing a high proportion of related primes and a low proportion of unrelated primes relative to a block containing the opposite mix (Bodner & Masson, 2001). In the present study, this phenomenon is explored with a parity (even/odd) decision task in which a prime (e.g., 2) precedes a target that can be either congruent (e.g., 4) or incongruent (e.g., 3). It is shown that the effect of congruence proportion with masked primes cannot be explained in terms of the blockwise prime-target contingency. Specifically, with masked primes, there is no congruency disadvantage in a block containing a high proportion of incongruent primes, but there is a congruency advantage when the block contains an equal proportion of congruent and incongruent primes. In qualitative contrast, visible primes are sensitive to the blockwise prime-target contingency. The authors explain the relatedness proportion effect found with masked primes in terms of a model according to which response-initiation processes adapt to the statistical structure of the environment, specifically the difficulty of recent trials. This account is supported with an analysis at the level of individual trials using the linear mixed effects model.


Single-pass percutaneous liver biopsy for diffuse liver disease using an automated device: experience in 154 procedures.
To describe our experience with ultrasound (US)-guided percutaneous liver biopsies using the INRAD 18 G Express core needle biopsy system. One hundred and fifty-four consecutive percutaneous core liver biopsy procedures were performed in 153 men in a single institution over 37 months. The medical charts, pathology reports, and radiology files were retrospectively reviewed. The number of needle passes, type of guidance, change in hematocrit level, and adequacy of specimens for histologic analysis were evaluated. All biopsies were performed for histologic staging of chronic liver diseases. The majority of patients had hepatitis C (134/153, 90.2%). All patients were discharged to home after 4 hr of post-procedural observation. In 145 of 154 (94%) biopsies, a single needle pass was sufficient for diagnosis. US guidance was utilized in all but one of the procedures (153/154, 99.4%). The mean hematocrit decrease was 1.2% (44.1--42.9%). Pain requiring narcotic analgesia, the most frequent complication, occurred in 28 of 154 procedures (18.2%). No major complications occurred. The specimens were diagnostic in 152 of 154 procedures (98.7%). Single-pass percutaneous US-guided liver biopsy with the INRAD 18 G Express core needle biopsy system is safe and provides definitive pathologic diagnosis of chronic liver disease. It can be performed on an outpatient basis. Routine post-biopsy monitoring of hematocrit level in stable, asymptomatic patients is probably not warranted.


Closure of persistent tracheocutaneous fistula following "starplasty" tracheostomy in children.
The "starplasty" technique of pediatric tracheostomy was introduced in 1990 as an alternative pediatric tracheostomy technique associated with several advantages. The only apparent drawback of this technique is the higher incidence of persistent tracheocutaneous fistula following decannulation. Several methods have been proposed for closure of persistent tracheocutaneous fistula in children, including fistulectomy with primary closure and fistulectomy with healing by secondary intent. Some authors advocate placement of a drain at the time of primary closure. We present our experience with closure of persistent tracheocutaneous fistula following starplasty in children over the past 15 years. Ninety-six starplasty procedures were performed on 96 children from 1990 to present, all by the senior author or under the guidance of the senior author. Twenty-eight of these children have been decannulated. Three fistulas closed spontaneously following decannulation. Of the remaining 25 children, 13 have undergone surgical closure of the tracheocutaneous fistula by the senior author. All tracheocutaneous fistula closures were performed as a fistulectomy with primary closure in three layers. Drains were not used in any of the patients. There were three minor complications in the postoperative period (wound infection and airway granuloma) and no major complications. None of the patients have experienced any degree of airway stenosis and there was no need for a repeat tracheotomy in any of the tracheocutaneous fistula closure patients. The cosmetic results were deemed to be good. "Starplasty" is a safe, reliable pediatric tracheostomy technique that has been shown to decrease the incidence of perioperative morbidity and mortality. The only drawback appears to be a high incidence of postoperative tracheocutaneous fistula. Our method of persistent tracheocutaneous fistula closure following starplasty is safe and effective, with no major complications and no incidence of postoperative airway narrowing.


Extending the timescale and range of ecosystem services through paleoenvironmental analyses, exemplified in the lower Yangtze basin.
In China, and elsewhere, long-term economic development and poverty alleviation need to be balanced against the likelihood of ecological failure. Here, we show how paleoenvironmental records can provide important multidecadal perspectives on ecosystem services (ES). More than 50 different paleoenvironmental proxy records can be mapped to a wide range of ES categories and subcategories. Lake sediments are particularly suitable for reconstructing records of regulating services, such as soil stability, sediment regulation, and water purification, which are often less well monitored. We demonstrate the approach using proxy records from two sets of lake sediment sequences in the lower Yangtze basin covering the period 1800-2006, combined with recent socioeconomic and climate records. We aggregate the proxy records into a regional regulating services index to show that rapid economic growth and population increases since the 1950s are strongly coupled to environmental degradation. Agricultural intensification from the 1980s onward has been the main driver for reducing rural poverty but has led to an accelerated loss of regulating services. In the case of water purification, there is strong evidence that a threshold has been transgressed within the last two decades. The current steep trajectory of the regulating services index implies that regional land management practices across a large agricultural tract of eastern China are critically unsustainable.


Tactile picture recognition by early blind children: the effect of illustration technique.
This study investigated factors that influenced haptic recognition of tactile pictures by early blind children. Such a research is motivated by the difficulty to identify tactile pictures, that is, two-dimensional representations of objects, while it is the most common way to depict the surrounding world to blind people. Thus, it is of great interest to better understand whether an appropriate representative technique can make objects' identification more effective and to what extent a technique is uniformly suitable for all blind individuals. Our objective was to examine the effects of three techniques used to illustrate pictures (raised lines, thermoforming, and textures), and to find out if their effect depended on participants' level of use of tactile pictures. Twenty-three early blind children (half with a regular or moderate level of use of tactile pictures, and half with either no use or infrequent use) were asked to identify 24 pictures of eight objects designed as the pictures currently used in the tactile books and illustrated using these three techniques. Results showed better recognition of textured pictures than of thermoformed and raised line pictures. Participants with regular or moderate use performed better than participants with no or infrequent use. Finally, the effect of illustration technique on picture recognition did not depend on prior use of tactile pictures. To conclude, early and frequent use of tactile material develops haptic proficiency and textures have a facilitating effect on picture recognition whatever the user level. Practical implications for the design of tactile pictures are discussed in the conclusion.


Widespread evidence of cooperative DNA binding by transcription factors in Drosophila development.
Regulation of eukaryotic gene transcription is often combinatorial in nature, with multiple transcription factors (TFs) regulating common target genes, often through direct or indirect mutual interactions. Many individual examples of cooperative binding by directly interacting TFs have been identified, but it remains unclear how pervasive this mechanism is during animal development. Cooperative TF binding should be manifest in genomic sequences as biased arrangements of TF-binding sites. Here, we explore the extent and diversity of such arrangements related to gene regulation during Drosophila embryogenesis. We used the DNA-binding specificities of 322 TFs along with chromatin accessibility information to identify enriched spacing and orientation patterns of TF-binding site pairs. We developed a new statistical approach for this task, specifically designed to accurately assess inter-site spacing biases while accounting for the phenomenon of homotypic site clustering commonly observed in developmental regulatory regions. We observed a large number of short-range distance preferences between TF-binding site pairs, including examples where the preference depends on the relative orientation of the binding sites. To test whether these binding site patterns reflect physical interactions between the corresponding TFs, we analyzed 27 TF pairs whose binding sites exhibited short distance preferences. In vitro protein-protein binding experiments revealed that >65% of these TF pairs can directly interact with each other. For five pairs, we further demonstrate that they bind cooperatively to DNA if both sites are present with the preferred spacing. This study demonstrates how DNA-binding motifs can be used to produce a comprehensive map of sequence signatures for different mechanisms of combinatorial TF action.


HIF takes it up a notch.
Notch signaling is used to choose cell fates in many developmental contexts. New evidence shows that circulating blood cells in Drosophila, in the absence of Notch ligand provided by neighboring cells, activate Notch signaling through stabilization with the hypoxia-inducible factor-α (HIF-α) transcription factor. Although HIF-α is a key regulator of the low-oxygen stress response, here it acts without its HIF-β partner by interacting with and stabilizing the Notch receptor. These roles for HIF-α and Notch are atypical in multiple ways, from the activity of HIF-α under normal oxygen tensions and without its partner HIF-β to the ligand-independent activity of Notch, and serve as a challenge to identify other noncanonical uses of well-studied signaling pathways.


Inhibition of sepsis-induced inflammatory response by β1-adrenergic antagonists.
Although previous studies have described potential benefits of nonselective β-adrenergic antagonist therapy in sepsis, there is a paucity of data on the use of β1-selective antagonists (B1AA). The purposes of this study were to describe the effects of B1AA on survival in septic animals and to explore for molecular mechanisms of potential treatment benefit. C57BL/6 male mice received intraperitoneal injection of lipopolysaccharide. Continuous infusion of a B1AA (esmolol) or an equal volume of saline (control) was initiated at 4 hours after injection. Kaplan-Meier survival analysis at 120 hours was used to explore for mortality differences. A subgroup of animals was sacrificed for microarray expression analysis. Top candidate genes were validated in vitro and in silico. Expression of our candidate genes in a human microarray database (GSE28750) was explored. B1AA infusion resulted in increased survival (p = 0.001) at 120 hours. Mean survival difference was 23.6 hours (p = 0.002). Hazard ratio for mortality with B1AA is 0.43 (95% confidence interval, 0.26-0.72). Immunologic disease (p = 0.0003-0.036) and cell death/survival (p = 0.0001-0.042) were significantly associated with improved survival in septic mice treated with B1AA. Further analysis of the gene structure revealed that eight genes shared common promoter activating sequence for NFKB and/or BRCA1 motifs. Analysis of a human sepsis database identified the up-regulation of CAMP (p = 0.032) and TNFSF10 (p = 0.001) genes in septic patients compared with healthy controls. Continuous infusion of a B1AA initiated after septic insult improves survival at 5 days in a murine model. Benefits may be caused by modulation of gene expression in immunologic pathways leading to an increase in CAMP and TNFSF10 expression. This observed effect may be explained by the activation of NFKB and BRCA1 genes involved in immune response and cell repair pathways. Our findings support further investigation of the use of B1AA in the treatment of sepsis.


Behavioral effects of long-term oral administration of aluminum ammonium sulfate in male and female C57BL/6J mice.
Aluminum (Al) is considered to be a neurotoxic metal, and excessive exposure to Al has been reported to be a potential risk factor for neurodegenerative diseases. Al ammonium sulfate is one of the Al compounds that is widely used as a food additive. However, the effects of the oral administration of Al ammonium sulfate on physical development and behavior remain to be examined. In this study, we investigated the effects of the administration of Al ammonium sulfate 12-water dissolved in drinking water (0.075 mg/mL) beginning in adolescence on various types of behavior in adult female C57BL/6J mice through a battery of behavioral tests (low-dose experiment; Experiment 1). We further examined the behavioral effects of the oral administration of a higher dose of the Al compound in drinking water (1 mg/mL) beginning in the prenatal period on behavior in adult male and female mice (high-dose experiment; Experiment 2). In the low-dose experiment, in which females' oral intake of Al was estimated to be 0.97 mg Al/kg/d as adults, Al-treated females exhibited an increase in total arm entries in the elevated plus maze test, an initial decrease and subsequent increase in immobility in the forced swim test, and reduced freezing in the fear conditioning test approximately 1 month after the conditioning session compared with vehicle-treated females (uncorrected P < .05). However, the behavioral differences did not reach a statistically significant level after correction for multiple testing. In the high-dose experiment, in which animals' oral intakes were estimated to be about ten times higher than those in the low-dose experiment, behavioral differences found in the low-dose experiment were not observed in high-dose Al-treated mice, suggesting that the results of the low-dose experiment might be false positives. Additionally, although high-dose Al-treated females exhibited increased social contacts with unfamiliar conspecifics and impaired reference memory performance, and high-dose Al-treated mice exhibited decreases in prepulse inhibition and in correct responses in the working memory task (uncorrected P < .05), the differences in any of the behavioral measures did not reach the significance level after correction for multiple testing. Our results show that long-term oral exposure to Al ammonium sulfate at the doses used in this study may have the potential to induce some behavioral changes in C57BL/6J mice. However, the behavioral effects of Al were small and statistically weak, as indicated by the fact that the results failed to reach the study-wide significance level. Thus, further study will be needed to replicate the results and reevaluate the behavioral outcomes of oral intake of Al ammonium sulfate.


Change and stability in contraceptive use patterns among US women over a 12-month period: analysis using the 2013-2015 National Survey of Family Growth life history calendar.
To improve understanding of contraceptive use over 1 year among women in the United States. We used the 2013-2015 National Survey of Family Growth to examine monthly contraceptive use patterns over a 12-month period. We focused on use of contraception during months in which non-sterilized women were sexually active and not pregnant; our outcomes were contraceptive use in every month, some months, and no months. We used simple and multivariate logistic regression to examine socio-demographic and method use characteristics associated with contraceptive use patterns. Some 72% of non-pregnant, non-surgically sterile women used contraception in every sexually active month. After controlling for other demographic and individual characteristics, adolescents had higher odds (aOR = 2.45) of using contraception in each sexually active month compared to women aged 25-29. Other groups more likely to use contraception monthly included those with some college (aOR = 1.58) compared to less than high school and non-cohabiting unmarried women (aOR = 1.49) compared to married women. Those with gaps in insurance coverage during the past year (aOR = 0.70), women who were not sexually active all 12 months (aOR = 0.42), and those with more than two male sexual partners (aOR = 0.49), were less likely to use contraception every sexually active month. Nearly half (46%) of contraceptive users in our sample used more than one type of contraceptive method over the 12-month period. The majority of women use contraception every month they are sexually active, although there is variation between socio-demographic groups. However, over a one-year period, many women used dynamic contraceptive strategies. Health care providers should recognize that contraceptive use patterns are dynamic and change over a relatively short time period for many women.


American Academy of Pediatrics: Falls from heights: windows, roofs, and balconies.
Falls of all kinds represent an important cause of child injury and death. In the United States, approximately 140 deaths from falls occur annually in children younger than 15 years. Three million children require emergency department care for fall-related injuries. This policy statement examines the epidemiology of falls from heights and recommends preventive strategies for pediatricians and other child health care professionals. Such strategies involve parent counseling, community programs, building code changes, legislation, and environmental modification, such as the installation of window guards and balcony railings.


Glycomic analysis of sialic acid linkages in glycans derived from blood serum glycoproteins.
A number of alterations to the normal glycomic profile have been previously described for a number of diseases and disorders, thus underscoring the medical importance of studying the glycans associated with proteins present in biological samples. An important alteration in cancer progression is an increased level of alpha2,6-sialylation, which aids in increasing the metastatic potential of tumor cells. Here we report a glycomic method that selectively amidates alpha2,6-linked sialic acids, while those that are alpha2,3-linked undergo spontaneous lactonization. Following subsequent permethylation, MALDI-TOF MS analysis revealed that many sialylated glycans present on glycoproteins found in blood serum featured increased levels of alpha2,6-sialylation in breast cancer samples. On the basis of the altered ratios of alpha2,3-linked to alpha2,6-linked sialic acids, many of these glycans became diagnostically relevant when they did not act as such indicators when based on traditional glycomic profiling alone.


Pneumocystis jirovecii pneumonia in non-HIV-infected patients in the era of novel immunosuppressive therapies.
In human immunodeficiency virus (HIV)-infected patients, Pneumocystis jirovecii pneumonia (PCP) is a well-known opportunistic infection, and its management has been established. However, PCP is an emerging threat to immunocompromised patients without HIV infection, such as those receiving novel immunosuppressive therapeutics for malignancy, organ transplantation, or connective tissue diseases. Clinical manifestations of PCP are quite different between patients with and without HIV-infections. In patients without HIV infection, PCP rapidly progresses, is difficult to diagnose correctly, and causes severe respiratory failure with a poor prognosis. High-resolution computed tomography findings are different between PCP patients with HIV infection and those without. These differences in clinical and radiologic features are the result of severe or dysregulated inflammatory responses that are evoked by a relatively small number of Pneumocystis organisms in patients without HIV infection. In recent years, the usefulness of PCR and serum β-D-glucan assay for rapid and noninvasive diagnosis of PCP has been revealed. Although corticosteroid adjunctive to anti-Pneumocystis agents has been shown to be beneficial in some populations, the optimal dose and duration remain to be determined. Recent investigations revealed that Pneumocystis colonization is prevalent, and that asymptomatic carriers are at riskfor developing PCP and can serve as the reservoir for the spread of Pneumocystis by person-to-person transmission. These findings suggest the need for chemoprophylaxis in immunocompromised patients without HIV infection, although its indication and duration are still controversial. Because a variety of novel immunosuppressive therapeutics have been emerging in medical practice, further innovations in the diagnosis and treatment of PCP are needed.


National income inequality predicts cultural variation in mouth to mouth kissing.
Romantic mouth-to-mouth kissing is culturally widespread, although not a human universal, and may play a functional role in assessing partner health and maintaining long-term pair bonds. Use and appreciation of kissing may therefore vary according to whether the environment places a premium on good health and partner investment. Here, we test for cultural variation (13 countries from six continents) in these behaviours/attitudes according to national health (historical pathogen prevalence) and both absolute (GDP) and relative wealth (GINI). Our data reveal that kissing is valued more in established relationships than it is valued during courtship. Also, consistent with the pair bonding hypothesis of the function of romantic kissing, relative poverty (income inequality) predicts frequency of kissing across romantic relationships. When aggregated, the predicted relationship between income inequality and kissing frequency (r = 0.67, BCa 95% CI[0.32,0.89]) was over five times the size of the null correlations between income inequality and frequency of hugging/cuddling and sex. As social complexity requires monitoring resource competition among large groups and predicts kissing prevalence in remote societies, this gesture may be important in the maintenance of long-term pair bonds in specific environments.


Better leukemia-free and overall survival in AML in first remission following cyclophosphamide in combination with busulfan compared with TBI.
Cyclophosphamide combined with total body irradiation (Cy/TBI) or busulfan (BuCy) are the most widely used myeloablative conditioning regimens for allotransplants. Recent data regarding their comparative effectiveness are lacking. We analyzed data from the Center for International Blood and Marrow Transplant Research for 1230 subjects receiving a first hematopoietic cell transplant from a human leukocyte antigen-matched sibling or from an unrelated donor during the years 2000 to 2006 for acute myeloid leukemia (AML) in first complete remission (CR) after conditioning with Cy/TBI or oral or intravenous (IV) BuCy. Multivariate analysis showed significantly less nonrelapse mortality (relative risk [RR] = 0.58; 95% confidence interval [CI]: 0.39-0.86; P = .007), and relapse after, but not before, 1 year posttransplant (RR = 0.23; 95% CI: 0.08-0.65; P = .006), and better leukemia-free survival (RR = 0.70; 95% CI: 0.55-0.88; P = .003) and survival (RR = 0.68; 95% CI: 0.52-0.88; P = .003) in persons receiving IV, but not oral, Bu compared with TBI. In combination with Cy, IV Bu is associated with superior outcomes compared with TBI in patients with AML in first CR.


Premature ovarian failure.
Premature ovarian failure (POF) is a primary ovarian defect characterized by absent menarche (primary amenorrhea) or premature depletion of ovarian follicles before the age of 40 years (secondary amenorrhea). It is a heterogeneous disorder affecting approximately 1% of women <40 years, 1:10,000 women by age 20 and 1:1,000 women by age 30. The most severe forms present with absent pubertal development and primary amenorrhea (50% of these cases due to ovarian dysgenesis), whereas forms with post-pubertal onset are characterized by disappearance of menstrual cycles (secondary amenorrhea) associated with premature follicular depletion. As in the case of physiological menopause, POF presents by typical manifestations of climacterium: infertility associated with palpitations, heat intolerance, flushes, anxiety, depression, fatigue. POF is biochemically characterized by low levels of gonadal hormones (estrogens and inhibins) and high levels of gonadotropins (LH and FSH) (hypergonadotropic amenorrhea). Beyond infertility, hormone defects may cause severe neurological, metabolic or cardiovascular consequences and lead to the early onset of osteoporosis. Heterogeneity of POF is also reflected by the variety of possible causes, including autoimmunity, toxics, drugs, as well as genetic defects. POF has a strong genetic component. X chromosome abnormalities (e.g. Turner syndrome) represent the major cause of primary amenorrhea associated with ovarian dysgenesis. Despite the description of several candidate genes, the cause of POF remains undetermined in the vast majority of the cases. Management includes substitution of the hormone defect by estrogen/progestin preparations. The only solution presently available for the fertility defect in women with absent follicular reserve is ovum donation.


A Review of the Potential Benefits of Increasing Vitamin D Status in Mongolian Adults through Food Fortification and Vitamin D Supplementation.
Serum 25-hydroxyvitamin D (25(OH)D) concentrations are low in Mongolia, averaging 22 ng/mL in summer and only 8 ng/mL in winter. Mongolians have high incidence and/or prevalence of several diseases linked to low 25(OH)D concentrations, including ischemic heart disease, malignant neoplasms, cirrhosis of the liver, ischemic stroke, lower respiratory tract infections, preterm birth complications, and diabetes mellitus. Fortifying regularly consumed foods such as flour, milk, and edible oils with vitamin D3 could raise 25(OH)D concentrations by about 10 ng/mL. However, to achieve 25(OH)D concentrations of 30-40 ng/mL in adults, vitamin D intakes of 1000 to 4000 IU/day would be required, making personal supplement use necessary. On the basis of prospective observational studies and clinical trials of disease incidence or known mortality rates and adverse pregnancy and birth outcomes, raising mean serum 25(OH)D concentrations to 40 ng/mL would likely reduce incidence and mortality rates for those and other diseases, reduce the rate of adverse pregnancy and birth outcomes, and increase mean life expectancy by one year or more.


Dietary patterns and their association with hypertension among Pakistani urban adults.
Hypertension is one of the most common chronic diseases affecting more than 25% of adults worldwide. In Pakistan, 33% of the adult population suffers from hypertension. Numerous epidemiological studies have demonstrated the critical role of dietary patterns in the causation, prevention and management of hypertension. There's a dearth of evidence from South Asia in this regard. The present study aimed to identify the association between dietary patterns and hypertension among 4304 low income urban adults who participated in the Control of Blood Pressure and Risk Attenuation (COBRA) study in Karachi, Pakistan. Dietary information was collected by a 33- item food frequency questionnaire and 3 unique dietary patterns namely; fat and sweet, fruit and vegetable, and seafood and yogurt patterns were derived using principal component factor analyses. We used univariate and multivariable logistic regression to examine the association between dietary patterns and hypertension. Men were more likely to have hypertension, while increase in age, and body mass index were also associated with hypertension (p<0.001). After adjusting for age, gender, education, marital status, body mass index, and tobacco use; the seafood and yogurt pattern was less likely (OR=0.78: 95% CI: 0.63, 0.98; p-value 0.03) to be associated with hypertension, whereas no significant associations were seen for other two dietary patterns. These findings suggest that certain dietary patterns may be associated with hypertension among Pakistani low income urban adults.


Highly productive infection with pseudotyped human immunodeficiency virus type 1 (HIV-1) indicates no intracellular restrictions to HIV-1 replication in primary human astrocytes.
Human astrocytes can be infected with human immunodeficiency virus type 1 (HIV-1) in vitro and in vivo, but, in contrast to T lymphocytes and macrophages, virus expression is inefficient. To investigate the HIV-1 life cycle in human fetal astrocytes, we infected cells with HIV-1 pseudotyped with envelope glycoproteins of either amphotropic murine leukemia virus or vesicular stomatitis virus. Infection by both pseudotypes was productive and long lasting and reached a peak of 68% infected cells and 1.7 microg of viral p24 per ml of culture supernatant 7 days after virus inoculation and then continued with gradually declining levels of virus expression through 7 weeks of follow-up. This contrasted with less than 0.1% HIV-1 antigen-positive cells and 400 pg of extracellular p24 per ml at the peak of astrocyte infection with native HIV-1. Cell viability and growth kinetics were similar in infected and control cells. Northern blot analysis revealed the presence of major HIV-1 RNA species of 9, 4, and 2 kb in astrocytes exposed to pseudotyped (but not wild-type) HIV-1 at 2, 14, and 28 days after infection. Consistent with productive infection, the 9- and 4-kb viral transcripts in astrocytes infected by pseudotyped HIV-1 were as abundant as the 2-kb mRNA during 4 weeks of follow-up, and both structural and regulatory viral proteins were detected in infected cells by immunoblotting or cell staining. The progeny virus released by these cells was infectious. These results indicate that the major barrier to HIV-1 infection of primary astrocytes is at virus entry and that astrocytes have no intrinsic intracellular restriction to efficient HIV-1 replication.


The innovative medicines initiative: a European response to the innovation challenge.
The Innovative Medicines Initiative (IMI) was launched in 2008 as a large-scale public-private partnership between the European Commission and the European Federation of Pharmaceutical Industries and Associations (EFPIA). With a total budget of €2 billion, the IMI aims to boost the development of new medicines across Europe by implementing new collaborative endeavors between large pharmaceutical companies and other key actors in the health-care ecosystem, i.e., academic institutions, small and medium enterprises, patients, and regulatory authorities. Projects conducted by IMI consortia have already delivered meaningful results, providing proof-of-concept evidence for the efficiency of this new model of collaboration. In this article we review recent achievements of the IMI consortia and discuss the growing interest in the IMI as a best-practice model to reinvigorate drug development.


Friendship and natural selection.
More than any other species, humans form social ties to individuals who are neither kin nor mates, and these ties tend to be with similar people. Here, we show that this similarity extends to genotypes. Across the whole genome, friends' genotypes at the single nucleotide polymorphism level tend to be positively correlated (homophilic). In fact, the increase in similarity relative to strangers is at the level of fourth cousins. However, certain genotypes are also negatively correlated (heterophilic) in friends. And the degree of correlation in genotypes can be used to create a "friendship score" that predicts the existence of friendship ties in a hold-out sample. A focused gene-set analysis indicates that some of the overall correlation in genotypes can be explained by specific systems; for example, an olfactory gene set is homophilic and an immune system gene set is heterophilic, suggesting that these systems may play a role in the formation or maintenance of friendship ties. Friends may be a kind of "functional kin." Finally, homophilic genotypes exhibit significantly higher measures of positive selection, suggesting that, on average, they may yield a synergistic fitness advantage that has been helping to drive recent human evolution.


Daily satisfaction with life is regulated by both physical activity and sedentary behavior.
Recent research revealed that on days when college students engage in more physical activity than is typical for them, they also experience greater satisfaction with life (SWL). That work relied on self-reported physical activity and did not differentiate between low levels of physical activity and sedentary behavior. This study was designed to (1) determine if the association between self-reported physical activity and SWL would exist when physical activity was monitored objectively and (2) examine the between- and within-person associations among physical activity, sedentary behavior, and SWL. During a 14-day ecological momentary assessment study, college students (N = 128) wore an accelerometer to objectively measure physical activity and sedentary behavior, and they self-reported their physical activity, sedentary behavior, and SWL at the end of each day. Physical activity and sedentary behavior had additive, within-person associations with SWL across self-reported and objective-measures of behavior. Strategies to promote daily well-being should encourage college students to incorporate greater amounts of physical activity as well as limit their sedentary behavior.


Statins enhance postischemic hyperemia in the skin circulation of hypercholesterolemic patients: a monitoring test of endothelial dysfunction for clinical practice?
The present study aims to investigate whether laser Doppler flowmetry can be used to monitor improvements in vascular function during statin therapy. Endothelial dysfunction is an early feature of atherosclerosis in hypercholesterolemic patients and can be improved by statins. There are several methods to assess endothelial function in vivo, none of them being feasible in everyday practice. Skin perfusion, measured by laser Doppler flowmetry, was assessed at rest and during reactive hyperemia. Nineteen hypercholesterolemic patients (age 42 to 73 years, total cholesterol 5.4 to 9.6 mmol/l) were studied before and during statin therapy. To further investigate the mechanisms, postischemic skin hyperemia was measured before and after intradermal injection of the nitric oxide synthase inhibitor L-NAME and its inactive isoform D-NAME (0.5 micromol/10 microl each). On a separate day, the healthy volunteers were reexamined before and 2 h after 1,000 mg aspirin. Postischemic skin blood flow was markedly reduced in hypercholesterolemic patients (45 +/- 11%) compared with healthy controls (238 +/- 20%, p < 0.0001) and improved after statin therapy (113 +/- 15%, p = 0.0005 vs. pre-treatment). In the healthy volunteers, the hyperemic responses were not significantly different after L-NAME and D-NAME. Aspirin reduced hyperemia from 274 +/- 49% to 197 +/- 40% (p = 0.025). Reactive hyperemia of the skin microcirculation can be easily and reproducibly assessed by laser Doppler flowmetry. Vasodilator prostaglandins are the major mediators of postischemic skin hyperemia, which is impaired in hypercholesterolemic patients and can be enhanced by cholesterol-lowering therapy. Thus, laser Doppler flowmetry may represent a tool to assess and monitor vascular function during therapy in everyday practice.


Rapid protein kinase D translocation in response to G protein-coupled receptor activation. Dependence on protein kinase C.
Protein kinase D (PKD)/protein kinase C (PKC) mu is a serine/threonine protein kinase that can be activated by physiological stimuli like growth factors, antigen-receptor engagement and G protein-coupled receptor (GPCR) agonists via a phosphorylation-dependent mechanism that requires PKC activity. In order to investigate the dynamic mechanisms associated with GPCR signaling, the intracellular translocation of a green fluorescent protein-tagged PKD was analyzed by real-time visualization in fibroblasts and epithelial cells stimulated with bombesin, a GPCR agonist. We found that bombesin induced a rapidly reversible plasma membrane translocation of green fluorescent protein-tagged PKD, an event that can be divided into two distinct mechanistic steps. The first step, which is exclusively mediated by the cysteine-rich domain in the N terminus of PKD, involved its translocation from the cytosol to the plasma membrane. The second step, i.e. the rapid reverse translocation of PKD from the plasma membrane to the cytosol, required its catalytic domain and surprisingly PKC activity. These findings provide evidence for a novel mechanism by which PKC coordinates the translocation and activation of PKD in response to bombesin-induced GPCR activation.


Expression of an immunogenic Ebola immune complex in Nicotiana benthamiana.
Filoviruses (Ebola and Marburg viruses) cause severe and often fatal haemorrhagic fever in humans and non-human primates. The US Centers for Disease Control identifies Ebola and Marburg viruses as 'category A' pathogens (defined as posing a risk to national security as bioterrorism agents), which has lead to a search for vaccines that could prevent the disease. Because the use of such vaccines would be in the service of public health, the cost of production is an important component of their development. The use of plant biotechnology is one possible way to cost-effectively produce subunit vaccines. In this work, a geminiviral replicon system was used to produce an Ebola immune complex (EIC) in Nicotiana benthamiana. Ebola glycoprotein (GP1) was fused at the C-terminus of the heavy chain of humanized 6D8 IgG monoclonal antibody, which specifically binds to a linear epitope on GP1. Co-expression of the GP1-heavy chain fusion and the 6D8 light chain using a geminiviral vector in leaves of N. benthamiana produced assembled immunoglobulin, which was purified by ammonium sulphate precipitation and protein G affinity chromatography. Immune complex formation was confirmed by assays to show that the recombinant protein bound the complement factor C1q. Size measurements of purified recombinant protein by dynamic light scattering and size-exclusion chromatography also indicated complex formation. Subcutaneous immunization of BALB/C mice with purified EIC resulted in anti-Ebola virus antibody production at levels comparable to those obtained with a GP1 virus-like particle. These results show excellent potential for a plant-expressed EIC as a human vaccine.


Anthelmintic resistance and management of nematode parasites on beef cattle-rearing farms in the North Island of New Zealand.
To provide information on current farmers' opinions and farming practices thought to be related to anthelmintic resistance, and to test for associations between the presence of anthelmintic resistance and management practices on beef-cattle rearing farms in the North Island of New Zealand. A study using an interview-based questionnaire about management of internal parasites was conducted on 62 beef cattle-rearing farms in the North Island of New Zealand, using case-control analyses to test for associations between management practices and the presence or absence of resistance to ivermectin or albendazole. Resistance was inferred from faecal nematode egg count (FEC) reduction (FECR) tests (FECRTs) when there was <90% reduction in FEC 7-10 days after treatment of calves <12 months of age. Of the 59 farmers who completed the questionnaire, most (n=40) ranked parasites highly, and at about the same level as quality and quantity of feed, as important production-limiting factors for their enterprises. In contrast, anthelmintic resistance was not perceived to be a problem on 13 farms, and its importance was rated low on 24, moderate on 15, and high on only six farms. Despite all farms having planned parasite control programmes, there was heavy reliance on clinical signs of parasitism to determine frequency of treatments. About one in three farmers with beef breeder cows routinely treated their calves at marking, one in five treated mixed-age cows, and almost half treated rising 2-year-old cows before calving. One in four farmers used anthelmintics on calves on 8-12 occasions in their first year of life. Co-grazing with other species was rare, but follow-on grazing within 3 months after older cattle or sheep was common. On most farms, grazing cattle was restricted to part of the farm, a finding with implications for parasite control and persistence of larvae in refugia. Macrocyclic lactone (ML) anthelmintics or their combinations with other action families were currently, and for the past 5 years, used more frequently than benzimidazoles and levamisole, and benzimidazole-levamisole combinations. The prevalence of resistance to ivermectin was high (82%) and no plausible model of associations could be constructed from the data. The prevalence of resistance to albendazole was 60%, and the risk of resistance increased as the number of rising 1-year-old cattle present mid-winter increased, and decreased as the number of breeding cows >2 years old present mid-winter increased. It is clear that in practice anthelmintic resistance is a secondary consideration to obtaining productivity advantages from the use of anthelmintics in beef cattle. Farmers' opinions were divided on many issues and the overall impression was of confused and diverse thinking regarding the principles of the use of anthelmintics. The overall outlook regarding anthelmintic resistance in cattle is bleak unless the need for integrated and long-term research activities is acted upon soon.


Aedes albopictus mosquito: the main vector of the 2007 Chikungunya outbreak in Gabon.
The primary vector at the origin of the 2007 outbreak in Libreville, Gabon is identified as Aedes albopictus, trapped around the nearby French military camp. The Chikungunya virus was isolated from mosquitoes and found to be identical to the A226V circulating human strain. This is the first field study showing the role of the recently arrived species Aedes albopictus in Chikungunya virus transmission in Central Africa, and it demonstrates this species' role in modifying the epidemiological presentation of Chikungunya in Gabon.


Translocation and utilization of fungal storage lipid in the arbuscular mycorrhizal symbiosis.
The arbuscular mycorrhizal (AM) symbiosis is responsible for huge fluxes of photosynthetically fixed carbon from plants to the soil. Carbon is transferred from the plant to the fungus as hexose, but the main form of carbon stored by the mycobiont at all stages of its life cycle is triacylglycerol. Previous isotopic labeling experiments showed that the fungus exports this storage lipid from the intraradical mycelium (IRM) to the extraradical mycelium (ERM). Here, in vivo multiphoton microscopy was used to observe the movement of lipid bodies through the fungal colony and to determine their sizes, distribution, and velocities. The distribution of lipid bodies along fungal hyphae suggests that they are progressively consumed as they move toward growing tips. We report the isolation and measurements of expression of an AM fungal expressed sequence tag that encodes a putative acyl-coenzyme A dehydrogenase; its deduced amino acid sequence suggests that it may function in the anabolic flux of carbon from lipid to carbohydrate. Time-lapse image sequences show lipid bodies moving in both directions along hyphae and nuclear magnetic resonance analysis of labeling patterns after supplying 13C-labeled glycerol to either extraradical hyphae or colonized roots shows that there is indeed significant bidirectional translocation between IRM and ERM. We conclude that large amounts of lipid are translocated within the AM fungal colony and that, whereas net movement is from the IRM to the ERM, there is also substantial recirculation throughout the fungus.


Chronic disease risk factors, healthy days and medical claims in South African employees presenting for health risk screening.
Non-communicable diseases (NCD) accounts for more than a third (37%) of all deaths in South Africa. However, this burden of disease can be reduced by addressing risk factors. The aim of this study was to determine the health and risk profile of South African employees presenting for health risk assessments and to measure their readiness to change and improve lifestyle behaviour. Employees (n = 1954) from 18 companies were invited to take part in a wellness day, which included a health-risk assessment. Self-reported health behaviour and health status was recorded. Clinical measures included cholesterol finger-prick test, blood pressure and Body Mass Index (BMI). Health-related age was calculated using an algorithm incorporating the relative risk for all case mortality associated with smoking, physical activity, fruit and vegetable intake, BMI and cholesterol. Medical claims data were obtained from the health insurer. The mean percentage of participation was 26% (n = 1954) and ranged from 4% in transport to 81% in the consulting sector. Health-related age (38.5 +/- 12.9 years) was significantly higher than chronological age (34.9 +/- 10.3 yrs) (p < 0.001). Both chronological and risk-related age were significantly different between the sectors (P < 0.001), with the manufacturing sector being the oldest and finance having the youngest employees. Health-related age was significantly associated with number of days adversely affected by mental and physical health, days away from work and total annual medical costs (p < 0.001). Employees had higher rates of overweight, smoking among men, and physical inactivity (total sample) when compared the general SA population. Increased health-related expenditure was associated with increased number of risk factors, absenteeism and reduced physical activity. SA employees' health and lifestyle habits are placing them at increased risk for NCD's, suggesting that they may develop NCD's earlier than expected. Inter-sectoral differences for health-related age might provide insight into those companies which have the greatest need for interventions, and may also assist in predicting future medical expenditure. This study underscores the importance of determining the health and risk status of employees which could assist in identifying the appropriate interventions to reduce the risk of NCD's among employees.


On the species of origin: diagnosing the source of symbiotic transcripts.
Most organisms have developed ways to recognize and interact with other species. Symbiotic interactions range from pathogenic to mutualistic. Some molecular mechanisms of interspecific interaction are well understood, but many remain to be discovered. Expressed sequence tags (ESTs) from cultures of interacting symbionts can help identify transcripts that regulate symbiosis, but present a unique challenge for functional analysis. Given a sequence expressed in an interaction between two symbionts, the challenge is to determine from which organism the transcript originated. For high-throughput sequencing from interaction cultures, a reliable computational approach is needed. Previous investigations into GC nucleotide content and comparative similarity searching provide provisional solutions, but a comparative lexical analysis, which uses a likelihood-ratio test of hexamer counts, is more powerful. Validation with genes whose origin and function are known yielded 94% accuracy. Microbial (non-plant) transcripts comprised 75% of a Phytophthora sojae-infected soybean (Glycine max cv Harasoy) library, contrasted with 15% or less in root tissue libraries of Medicago truncatula from axenic, Phytophthora medicaginis-infected, mycorrhizal, and rhizobacterial treatments. Mycorrhizal libraries contained about 23% microbial transcripts; an axenic plant library contained a similar proportion of putative microbial transcripts. Comparative lexical analysis offers numerous advantages over alternative approaches. Many of the transcripts isolated from mixed cultures were of unknown function, suggesting specificity to symbiotic metabolism and therefore candidates likely to be interesting for further functional investigation. Future investigations will determine whether the abundance of non-plant transcripts in a pure plant library indicates procedural artifacts, horizontally transferred genes, or other phenomena.


Longitudinal in vitro surveillance of Plasmodium falciparum sensitivity to common anti-malarials in Thailand between 1994 and 2010.
Drug and multidrug-resistant Plasmodium falciparum malaria has existed in Thailand for several decades. Furthermore, Thailand serves as a sentinel for drug-resistant malaria within the Greater Mekong sub-region. However, the drug resistance situation is highly dynamic, changing quickly over time. Here parasite in vitro drug sensitivity is reported for artemisinin derivatives, mefloquine, chloroquine and quinine, across Thailand. Blood was drawn from patients infected with P. falciparum in seven sentinel provinces along Thai international borders with Cambodia, Myanmar, Laos, and Malaysia. In vitro parasite sensitivity was tested using the World Health Organization's microtest (mark III) (between 1994 and 2002) and the histidine-rich protein-2 (HRP2)-based enzyme-linked immunosorbent assay (in 2010). Following World Health Organization protocol, at least 30 isolates were collected for each province and year represented in this study. Where possible, t-tests were used to test for significant differences. There appears to be little variation across study sites with regard to parasite sensitivity to chloroquine. Quinine resistance appears to have been rising prior to 1997, but has subsequently decreased. Mefloquine sensitivity appears high across the provinces, especially along the north-western border with Myanmar and the eastern border with Cambodia. Finally, the data suggest that parasite sensitivity to artemisinin and its derivatives is significantly higher in provinces along the north-western border with Myanmar. Parasite sensitivity to anti-malarials in Thailand is highly variable over time and largely mirrors official drug use policy. The findings with regard to reduced sensitivity to artemisinin derivatives are supported by recent reports of reduced parasite clearance associated with artemisinin. This trend is alarming since artemisinin is considered the last defence against malaria. Continued surveillance in Thailand, along with increased collaboration and surveillance across the entire Greater Mekong sub-region, is clearly warranted.


Spatial S-R compatibility effects in an intentional imitation task.
The active intermodal mapping hypothesis suggests that intentional imitation is mediated by a highly efficient, special-purpose mechanism of actor-centered movement encoding. In the present study, using methods from stimulus-response (S-R) compatibility research, we found no evidence to support this hypothesis. In two experiments, the performance of adult participants instructed to imitate actor-centered spatial properties of head, arm, and leg movements was affected by task-irrelevant, egocentric spatial cues. In Experiment 1, participants imitated using the same side of their bodies as did the model, and performance was less accurate when egocentric stimulus location was response incompatible than when it was response compatible. This effect was reversed in Experiment 2 when participants imitated using the opposite side of their bodies. These findings, in line with general process theories of imitation, imply that intentional imitation is mediated by the same processes that mediate responding to inanimate stimuli on the basis of arbitrary S-R mappings.


VEGF as a key mediator of angiogenesis in cancer.
Vascular endothelial growth factor (VEGF) is a homodimeric glycoprotein with a molecular weight of approximately 45 kDa. It is the key mediator of angiogenesis (the formation of new blood vessels), and binds two VEGF receptors (VEGF receptor-1 and VEGF receptor-2), which are expressed on vascular endothelial cells. In healthy humans, VEGF promotes angiogenesis in embryonic development and is important in wound healing in adults. VEGF is the key mediator of angiogenesis in cancer, in which it is up-regulated by oncogene expression, a variety of growth factors and also hypoxia. Angiogenesis is essential for cancer development and growth: before a tumor can grow beyond 1-2 mm, it requires blood vessels for nutrients and oxygen. The production of VEGF and other growth factors by the tumor results in the 'angiogenic switch', where new vasculature is formed in and around the tumor, allowing it to grow exponentially. Tumor vasculature formed under the influence of VEGF is structurally and functionally abnormal. Blood vessels are irregularly shaped, tortuous, have dead ends and are not organized into venules, arterioles and capillaries. They are also leaky and hemorrhagic, which leads to high interstitial pressure. These characteristics mean that tumor blood flow is suboptimal, resulting in hypoxia and further VEGF production. This central role of VEGF in the production of tumor vasculature makes it a rational target for anticancer therapy.


Accumulation properties of inorganic mercury and organic mercury in the red-crowned crane Grus japonensis in east Hokkaido, Japan.
The red-crowned (Japanese) crane Grus japonensis is native to east Hokkaido, Japan, in contrast to the East Asia mainland. Previously, we reported that red-crowned cranes in Hokkaido were highly contaminated with mercury in the 1990s and that the contamination rapidly decreased to a moderate level in the 2000s. In the present study, we determined levels of organic mercury (O-Hg) in the liver and kidney of cranes in east Hokkaido in comparison with levels of total mercury (T-Hg). T-Hg levels in the kidneys were higher than those in the livers in adults but not in subadults and juveniles; however, the reverse was the case for O-Hg even for adults. The ratio of O-Hg to T-Hg in both the liver and kidney decreased as T-Hg increased in the three developmental stages. While the ratios of O-Hg to T-Hg in the liver and kidney of adults were significantly lower than those of juveniles, the ratios were similar for adults and juveniles in a lower range of T-Hg. The ratio of selenium (Se) to T-Hg decreased as T-Hg increased in both the liver and kidney, irrespective of stages. Mercury burdens in feathers were about 59% and 67% of the total body burdens for juveniles and adults, respectively. Furthermore, ratios of carbon and nitrogen stable isotopes to T-Hg varied greatly, with no relation to mercury level in the liver. The results suggest slow accumulation of inorganic mercury in the kidney of red-crowned cranes in east Hokkaido, Japan.


Coupled defects in one-dimensional photonic crystal films fabricated with glancing angle deposition.
This work presents the successful fabrication of 1D photonic crystals (PCs) with two defects using the glancing angle deposition (GLAD) technique. We study the coupling behavior of the two PC defects and demonstrate the ability to control the defect interaction. GLAD allows engineering of film nanostructure to produce PCs with sinusoidal refractive index variation through control of film nanostructure and porosity. Two phase-shift defects are introduced into the refractive index profile of the film. The observed defect-defect coupling is explained by a coupled-oscillator model and the interaction strength is found to decrease exponentially with increasing defect separation. Furthermore, the results demonstrate the promise of GLAD as a platform technology for PC research and device fabrication.


Chemical composition and biological activity of star anise Illicium verum extracts against maize weevil, Sitophilus zeamais adults.
This study aims to develop eco-friendly botanical pesticides. Dried fruits of star anise (Illicium verum Hook.f. (Austrobaileyales: Schisandraceae)) were extracted with methyl alcohol (MA), ethyl acetate (EA), and petroleum ether (PE) at 25°C. The constituents were determined by gas chromatography-mass spectrometry, and the repellency and contact toxicity of the extracts against Sitophilus zeamais Motschulsky (Coleoptera: Curculionidae) adults were tested. Forty-four compounds, whose concentrations were more than 0.2%, were separated and identified from the MA, EA, and PE extracts. The extraction yields of trans-anethole, the most abundant biologically active compound in I. verum, were 9.7%, 7.5%, and 10.1% in the MA, EA, and PE extracts, respectively. Repellency increased with increasing extract dose. The average repellency rate of the extracts against S. zeamais adults peaked at 125.79 µg/cm(2) 72 hr after treatment. The percentage repellency of the EA extract reached 76.9%, making it a class IV repellent. Contact toxicity assays showed average mortalities of 85.4% (MA), 94.5% (EA), and 91.1% (PE). The EA extract had the lowest median lethal dose, at 21.2 µg/cm(2) 72 hr after treatment. The results suggest that I. verum fruit extracts and trans-anethole can potentially be developed as a grain protectant to control stored-product insect pests. Other active constituents in the EA extract merit further research.


Protective effects from Houttuynia cordata aqueous extract against acetaminophen-induced liver injury.
Protective effects of Houttuynia cordata aqueous extract (HCAE) against acetaminophen-induced hepatotoxicity in Balb/cA mice were examined. HCAE, at 1 or 2 g/L, was added into the drinking water for 4 weeks. Acute liver injury was induced by acetaminophen treatment intraperitoneally (350 mg/kg body weight). Acetaminophen treatment significantly depleted hepatic glutathione (GSH) content, increased hepatic malonyldialdehyde (MDA), reactive oxygen species (ROS) and oxidized glutathione (GSSG) levels, and decreased hepatic activity of glutathione peroxidase (GPX), catalase and superoxide dismutase (SOD) (p<0.05). The pre-intake of HCAE alleviated acetaminophen-induced oxidative stress by retaining GSH content, decreasing MDA, ROS and GSSG production, and maintaining activity of GPX, catalase and SOD in liver (p<0.05). The pre-intake of HCAE also significantly lowered acetaminophen-induced increase in cytochrome P450 2E1 activity (p<0.05). Acetaminophen treatment increased hepatic release of interleukin (IL)-6, IL-10, tumor necrosis factor (TNF)-alpha and monocyte chemoattractant protein-1 (p<0.05). HCAE intake significantly diminished acetaminophen-induced elevation of these cytokines (p<0.05). These results support that HCAE could provide hepato-protection.


Hydrogen-Rich Saline Inhibits Lipopolysaccharide-Induced Acute Lung Injury and Endothelial Dysfunction by Regulating Autophagy through mTOR/TFEB Signaling Pathway.
Hydrogen-rich saline (HRS) has strong anti-inflammatory, antioxidative stress, and antiapoptotic properties. The study focused on the protection of HRS on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in rat models and the relationship with autophagic regulation and mTOR/TFEB signaling pathway. Material and Methods. The LPS-induced ALI rats' model was established. Pathohistological change in lung tissue was detected by hematoxylin-eosin staining. The inflammatory cytokines were examined by enzyme-linked immunosorbent assay (ELISA). The key apoptosis proteins and autophagy-relevant proteins were analyzed by western blotting. In vitro, HPMEC models of ALI were treated with LPS. The inflammatory cytokines were detected. Apoptosis rate was determined by flow cytometry. The autophagy and mTOR/TFEB signaling pathway-related proteins were detected by western blot and immunohistochemical staining. HRS attenuated LPS-induced ALI and apoptosis both in vivo and in vitro. HRS attenuated inflammatory response, inhibited apoptosis, induced and activated autophagy in LPS-induced ALI model, and downregulated mTOR/TFEB signaling pathway. The protection of HRS can be blocked by autophagy inhibitor. Moreover, mTOR activator reversed HRS protection and mTOR inhibitor enhanced HRS protection in LPS-induced model and HRS activated autophagy via mTOR/TFEB signaling pathway. The results confirmed the protection of HRS in LPS-induced ALI by regulating apoptosis through inhibiting the mTOR/TFEB signaling pathway.


Dentofacial transverse development in Koreans according to skeletal maturation: A cross-sectional study.
The aim of this study was to establish the normative data of dentofacial transverse dimensions according to the skeletal maturation stage in Korean adolescents with good occlusion, assess gender differences and determine correlations between transverse variables. A total of 577 Korean subjects between ages 7 to 19 years and exhibiting skeletal Class I occlusion were categorized by skeletal maturation index (SMI) of Fishman using hand-wrist radiographs. Dentofacial transverse dimensions were assessed using posteroanterior cephalograms. Independent two-sample t-tests were used to analyze differences between genders. Pearson correlation coefficient was used to determine the correlation between transverse measurements. Dentofacial transverse norms relevant to skeletal maturation stages were established. The average maxillomandibular width difference and ratio at growth completion was 22.16 mm and 77.01% for males; 23.70 mm and 74.06% for females, respectively. Males had greater facial, maxillary and mandibular widths compared to females at every SMI stage. The maxillary and mandibular intermolar widths showed the strongest correlation for both sexes (r = 0.826 for males, r = 0.725 for females). Dentofacial transverse norms of Korean adolescents were established according to developmental stage. All dentofacial widths were greater in males at growth completion. Maxillary and mandibular intermolar widths were strongly correlated. This study may serve as a guideline for the assessment of dentofacial transverse growth according to skeletal maturation stage in Korean adolescents with good occlusion.


The immediate effect of musculoskeletal physiotherapy techniques and massage on pain and ease of breathing in adults with cystic fibrosis.
The optimal treatment approach to musculoskeletal pain in cystic fibrosis remains unclear. This study aimed to examine the effect of a combination of musculoskeletal physiotherapy techniques and massage therapy on musculoskeletal pain and ease of breathing. A single treatment session was associated with reduction in pain and improvement in ease of breathing in adults with cystic fibrosis.


PHR1, an integral membrane protein of the inner ear sensory cells, directly interacts with myosin 1c and myosin VIIa.
By using the yeast two-hybrid technique, we identified a candidate protein ligand of the myosin 1c tail, PHR1, and found that this protein can also bind to the myosin VIIa tail. PHR1 is an integral membrane protein that contains a pleckstrin homology (PH) domain. Myosin 1c and myosin VIIa are two unconventional myosins present in the inner ear sensory cells. We showed that PHR1 immunoprecipitates with either myosin tail by using protein extracts from cotransfected HEK293 cells. In vitro binding assays confirmed that PHR1 directly interacts with these two myosins. In both cases the binding involves the PH domain. In vitro interactions between PHR1 and the myosin tails were not affected by the presence or absence of Ca2+ and calmodulin. Finally, we found that PHR1 is able to dimerise. As PHR1 is expressed in the vestibular and cochlear sensory cells, its direct interactions with the myosin 1c and VIIa tails are likely to play a role in anchoring the actin cytoskeleton to the plasma membrane of these cells. Moreover, as both myosins have been implicated in the mechanotransduction slow adaptation process that takes place in the hair bundles, we propose that PHR1 is also involved in this process.


Telerheumatology--diagnostic accuracy and acceptability to patient, specialist, and general practitioner.
This study examines the diagnostic accuracy and acceptability of telemedicine in the field of rheumatology. One hundred patients had a telephone and televisual consultation and the results were compared with a face-to-face consultation. While the telephone consultations were often unsatisfactory, the televisual consultations were highly accurate (97%) and acceptable to patients, general practitioners, and specialists.


Feasibility of near infrared transmittance spectroscopy to predict fatty acid composition of commercial processed meat.
The new European Regulation 1169/2011 concerning nutrition declaration of food products compels the addition of saturated fatty acids, whereas the declaration of monounsaturated and polyunsaturated fatty acids remains voluntary. Therefore, the industry is interested in a more rapid, easy and less cost-effective analysis method for accomplishing this labelling regulation. The present study aimed to evaluate the ability of near infrared transmittance spectroscopy (wavelengths between 850 and 1050 nm) to predict the fatty acid (FA) composition of commercial processed meat samples (n = 310). Good predictions were achieved for the absolute content of saturated, unsaturated, monounsaturated and polyunsaturated FA, as well as ω-6 groups, and also for a few individual FA (C16:0, C18:0, C18:1n9, C18:2n6 and 18:1n7), with the coefficient of determination in cross-validation being > 0.90 and the residual prediction deviation being > 3.15. Unsatisfactory models were obtained for the relative content of FA. Near infrared transmittance spectroscopy can be considered as a reliable method for predicting the main groups of FA in processed meat products, whereas predictions of individual FA are less reliable. © 2017 Society of Chemical Industry.


MicroRNA-155 Protects Group 2 Innate Lymphoid Cells From Apoptosis to Promote Type-2 Immunity.
Group-2 innate lymphoid cells (ILC2) play critical roles in the initiation and maintenance of type-2 immune responses, predominantly through their production of the type-2 cytokines IL-5, IL-9, and IL-13. ILC2 are essential for the efficient elimination of helminth parasites, but also contribute to the detrimental type-2 immune responses that underlie diseases such as asthma and allergy. While several transcription factors have been identified that regulate the development and function of ILC2, less is known about the post-transcriptional mechanisms that regulate these processes. We identified micro-RNAs (miRNAs) that are co-ordinately regulated in ILC2 from mice exposed to two different stimuli, namely IL-33 "alarmin" administration or Nippostrongylus brasiliensis parasitic worm infection. miR-155 is upregulated in ILC2 in response to both stimuli and miR-155-/- mice had impaired IL-33-driven ILC2 responses. Using mixed bone marrow chimeras, we demonstrate that this deficit is intrinsic to ILC2 and that miR-155 protects ILC2 from apoptosis, while having little impact on ILC2 proliferation or cytokine production. These data reveal a subset of miRNAs that are regulated upon ILC2 activation and establish a specific role for miR-155 in regulating ILC2 survival following activation.


Screening and diagnosis of optic pathway gliomas in children with neurofibromatosis type 1 by using sweep visual evoked potentials.
Neurofibromatosis type 1 (NF-1) is an autosomal dominant phakomatosis with a prevalence of 1 in 2000 to 1 in 5000. Up to 24% of these patients have optic pathway gliomas (OPGs). In the present study, the use of sweep visual evoked potentials (SVEPs) was investigated as a screening tool for identifying patients with NF-1 who had OPGs by comparing them to those patients with no OPGs and to normally developing children. Contrast sensitivity and grating acuity were measured with the SVEP. Sixteen children with OPGs (OPG group), 14 children with NF-1 without OPGs (nOPG), and 16 aged-matched control subjects were recruited. All participants had best-corrected visual acuity of 6/9 or better. All were tested monocularly. Comparisons between groups by using the Tukey B test showed a significant reduction of mean log contrast sensitivity in the OPG group (1.55) compared with the nOPG (1.9, P = 0.006) and control (2.10, P < 0.001) group. There was no significant difference between the nOPG and control groups (P = 0.195). Grating acuity was comparable between groups, and no statistically significant differences were found. Log contrast sensitivity was moderately sensitive in identifying patients with OPG and was highly specific in screening out patients with no OPG. Children with OPGs have reduced contrast sensitivity when assessed using the SVEP. Children with no OPGs display no differences in visual functioning compared with control subjects. The findings suggest that the SVEP can be a useful and noninvasive screening tool for early detection of visual pathway gliomas in children with NF-1 and normal visual acuity.


Systematic detection of BMAA (β-N-methylamino-l-alanine) and DAB (2,4-diaminobutyric acid) in mollusks collected in shellfish production areas along the French coasts.
The neurotoxin β-N-methylamino-l-alanine (BMAA) is naturally present in some microalgal species in the marine environment. The accumulation of BMAA has widely been observed in filter-feeding bivalves that are known to consume primary producers constituting the base of complex aquatic food webs. This study was performed to assess the occurrence of BMAA and isomers in mollusks collected from nine representative shellfish production areas located on the three French coasts (Channel, Atlantic and Mediterranean sites). The use of a highly selective and sensitive HILIC-MS/MS method, with D5DAB as internal standard, revealed the systematic detection of BMAA and DAB, in concentrations ranging from 0.20 to 6.7 μg g(-1) dry weight of digestive gland tissues of mollusks. While we detected BMAA in four strains of diatoms in a previous study, here BMAA was only detected in one diatom species previously not investigated out of the 23 microalgal species examined (belonging to seven classes). The concentrations of BMAA and DAB in mussels and oysters were similar at different sampling locations and despite the high diversity of phytoplankton populations that mollusks feed on at these locations. Only small variations of BMAA and DAB levels were observed and these were not correlated to any of the phytoplankton species reported. Therefore, extensive research should be performed on both origin and metabolism of BMAA in shellfish. The levels observed in this study are similar to those found in other studies in France or elsewhere. A previous study had related such levels to a cluster of Amyotrophic Lateral Sclerosis in the South of France; hence the widespread occurrence of BMAA in shellfish from all coasts in France found in this study suggests the need for further epidemiological and toxicological studies to establish the levels that are relevant for a link between the consumption of BMAA-containing foodstuffs and neurodegenerative diseases.


Disturbances of diurnal rhythms of biogenic amines contents in hypothalamic nuclei as an evidence of neurotropic effects of enterotropic carcinogen 1,2-dimethylhydrazine.
Our data on the contents of norepinephrine (NE), dopamine (DA) and the metabolite of serotonin 5-hydroxyindoleacetic acid (5-HIAA) measured in the suprachiasmatic nuclei (SCN), preoptic area (PA) and median eminence (ME) of hypothalamus of rats after single subcutaneous injection of 1,2-dimethylhydrazine (DMH) as well as the effect of this carcinogen on formation of reactive oxygen species (ROS) in the PA are presented in this paper. Diurnal changes of DA in all studied brain structures and of NE in the PA have been observed in the control group. Their morning levels were higher than evening ones. Rhythms of 5-HIAA in the SCN and diurnal changes of ROS formation have been shown to have contrary changes in control. Both the morning (11 a.m.) and evening (11 p.m.) subcutaneous administration of DMH at the dose of 21 mg/kg of body weight resulted in changes of all rhythms observed in control. In some cases a phase shift was found, in others the rhythms of neurotransmitters and ROS formation disappeared entirely. The data obtained confirm the idea of dopaminergic and serotoninergic systems taking part in mechanisms of a response of the hypothalamic nuclei to non-photic stimuli. It is suggested that the effect of DMH on the content and diurnal rhythms of neurotransmitters in the hypothalamic structures under study is due to its affecting activities of the enzymes of biogenic amines synthesis, synaptic transmission, melatonin synthesis and secretion rhythms. The change in ROS formation that is caused by administration of DMH is likely to be due to a disturbance of diurnal rhythms of neurotransmitters that are one of the sources of formation of free radicals in the brain.


Seven days of ceftriaxone therapy is as effective as ten days' treatment for bacterial meningitis.
Seventy-nine children were enrolled in a study to compare seven vs ten days of ceftriaxone therapy for bacterial meningitis. On the basis of a computer-generated list of therapy assignments, 35 children with Haemophilus, pneumococcal, or group B streptococcal meningitis each were assigned to seven- or ten-day treatment regimens; nine children with meningococcal meningitis received seven days of therapy. The population characteristics and etiologic agents were similar for the two treatment groups, as were also the findings on examination and culture of cerebrospinal fluid at completion of therapy. There were no significant differences in the frequency and types of neurological complications between the two treatment groups; four patients in each group had two or more neurological abnormalities. The rates of nosocomial infections and prolonged and secondary fever were similar in those who received seven days of therapy compared with patients treated for the conventional ten days. Diarrhea occurred in 44% of those receiving the drug. Patients treated with the seven-day regimen were discharged from the hospital approximately two days earlier than those with the ten-day regimen.


Unplanned splenectomy--harbinger of complications.
Splenectomy alone or in combination with other major operative procedures has been implicated as the cause of excessive morbidity and mortality. We retrospectively studied 151 consecutive patients with splenectomy performed between 1985 and 1992. Subsets of patients according to indication for splenectomy were compared with a cohort of patients having elective open cholecystectomy. Morbidity with elective splenectomy (11.5%) was not significantly increased over that with elective open cholecystectomy (6.8%). Morbidity with nonelective splenectomy (40.4%) was increased when compared with that of elective splenectomy (11.5%) or with elective open cholecystectomy (6.8%). Mortality was significantly worse for nonelective (10.6%) than for elective splenectomy (1%). Nonelective splenectomy should be recognized as one event in a cascade of events leading to excessive morbidity and mortality. Splenectomy should not be implicated as the sole or primary cause of such excesses.


Do patients with gastrointestinal cancer want to decide where they have tests and surgery? A questionnaire study of provider choice.
Choice of provider has been an important strategy among policy makers, intended, in part, to drive improvements in quality and efficiency of healthcare. This study examined the information requirements, and decision-making experiences and preferences of patients who have had surgery for gastrointestinal cancer, to assess the status of provider choice in current practice. The single-item Control Preferences Scale was used to determine patients' experiences and preferences when being referred for tests, and choosing where to have surgery. Participants used a Likert scale to rate the importance of 23 information items covering a variety of structures, processes and outcomes at the hospital level and the department level. Participants were recruited by post and online. 463 responses were analysed. Patients reported very low levels of involvement in provider choice, with their doctor deciding where they underwent tests or surgery in 77.0% and 81.8% of cases, respectively. Over two-thirds of participants would have preferred greater involvement in provider choice than they experienced. Of note, patient age and education were not associated with reported preferences. Information on how long patients with cancer wait for treatment, annual operative volume and postoperative mortality rate, as well as retained foreign bodies and infection rates were considered very important. There was a substantial unmet desire for greater involvement in provider choice among study participants. Respondents attached particular importance to surgery-specific information. Efforts should be made to increase involvement of patients with gastrointestinal cancer in provider decisions, across primary and secondary care, to deliver more patient-centred care. The reported lack of patient involvement in provider choice suggests it is unlikely to be working as an effective lever to drive quality improvement at present.


Rate of shear of an ultrasonic oscillating rod viscosity probe.
Ultrasonic oscillating rod probes have recently been used by researchers to measure viscosity and/or density in fluids. However, in order to use such probes to characterise the rheological properties of fluids, it is necessary to define the shear rate produced by the probe. This paper proposes an analytical solution to estimate the shear rate of ultrasonic oscillating rod viscosity probes and a method to measure their maximum operational shear rate. A relationship is developed which relates the torsional surface velocity of an oscillating cylindrical rigid body to the rate of shear in its vicinity. The surface displacement and torsional surface velocity of a torsional probe of length 1000 mm and diameter 1mm were measured over the frequency range from 525 to 700 kHz using a laser interferometer and the maximum shear rate estimated. The reported work provides the basis for characterising shear rate for such probes, enabling their application for rheological investigations.


Dual-targeted contrast agent for US assessment of tumor angiogenesis in vivo.
To develop and validate a dual-targeted ultrasonographic (US) imaging agent with microbubbles (MBs) that attaches to both vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) and alpha(v)beta(3) integrin and to compare the US imaging signal obtained from dual-targeted MBs (MB(D)) with that from single-targeted MBs (MB(S)) in a murine model of tumor angiogenesis. Animal protocols were approved by the institutional Administrative Panel on Laboratory Animal Care. Single- and dual-targeted US imaging agents were prepared by attaching anti-VEGFR2, anti-alpha(v)beta(3) integrin, or both antibodies to the shell of perfluorocarbon-filled MBs. Binding specificities of targeted MBs compared with isotype-matched immunoglobulin G-labeled control MBs (MB(C)) and nontargeted nonlabeled MBs (MB(N)) were tested with VEGFR2-positive and alpha(v)beta(3) integrin-positive cells (mouse SVR cells) and control cells (mouse 4T1 cells). In vivo imaging signals of contrast material-enhanced US by using anti-VEGFR2-targeted MBs (MB(V)), anti-alpha(v)beta(3) integrin-targeted MBs (MB(I)), MB(D), and MB(C) were quantified in 49 mice bearing SK-OV-3 tumors (human ovarian cancer). Tumor tissue was stained for VEGFR2, alpha(v)beta(3) integrin, and CD31. Attachment of MB(D) to SVR cells (mean, 0.74 MBs per cell +/- 0.05 [standard deviation]) was significantly higher than attachment to 4T1 cells (mean, 0.04 +/- 0.03), and attachment to SVR cells was higher for MB(D) than for MB(V) (mean, 0.58 +/- 0.09), MB(I) (mean, 0.42 +/- 0.21), MB(C) (mean, 0.11 +/- 0.13), and MB(N) (mean, 0.01 +/- 0.01) (P < .05). Imaging signal in the murine tumor angiogenesis model was significantly higher (P < .001) for MB(D) (mean, 16.7 +/- 7.2) than for MB(V) (mean, 11.3 +/- 5.7), MB(I) (mean, 7.8 +/- 5.3), MB(C) (mean, 2.8 +/- 0.9), and MB(N) (mean, 1.1 +/- 0.4). Immunofluorescence confirmed expression of VEGFR2 and alpha(v)beta(3) integrin on tumor vasculature. Dual-targeted contrast-enhanced US directed at both VEGFR2 and alpha(v)beta(3) integrin improves in vivo visualization of tumor angiogenesis in a human ovarian cancer xenograft tumor model in mice. http://radiology.rsnajnls.org/cgi/content/full/248/3/936/DC1.


Assessment of whole genome amplification for sequence capture and massively parallel sequencing.
Exome sequence capture and massively parallel sequencing can be combined to achieve inexpensive and rapid global analyses of the functional sections of the genome. The difficulties of working with relatively small quantities of genetic material, as may be necessary when sharing tumor biopsies between collaborators for instance, can be overcome using whole genome amplification. However, the potential drawbacks of using a whole genome amplification technology based on random primers in combination with sequence capture followed by massively parallel sequencing have not yet been examined in detail, especially in the context of mutation discovery in tumor material. In this work, we compare mutations detected in sequence data for unamplified DNA, whole genome amplified DNA, and RNA originating from the same tumor tissue samples from 16 patients diagnosed with non-small cell lung cancer. The results obtained provide a comprehensive overview of the merits of these techniques for mutation analysis. We evaluated the identified genetic variants, and found that most (74%) of them were observed in both the amplified and the unamplified sequence data. Eighty-nine percent of the variations found by WGA were shared with unamplified DNA. We demonstrate a strategy for avoiding allelic bias by including RNA-sequencing information.


A Phase II study of S-1 plus oral leucovorin in heavily treated metastatic colorectal cancer patients.
Fewer treatment options are available for refractory metastatic colorectal cancer (mCRC). In early trials, S-1 monotherapy was effective for mCRC patients after chemotherapy failure and its combination with oral leucovorin therapy offers promising results in untreated mCRC. Hence, we conduct a Phase II trial to assess the efficacy of S-1 plus oral leucovorin (SL) in refractory mCRC that progressed after multiple prior standard therapies. In this open-label, single-arm study, we enrolled the refractory mCRC patients who received fluoropyrimidine, oxaliplatin, and irinotecan treatment and at least one targeted therapy previously. The doses of SL were 40-60 and 30 mg twice daily separately. They were administered for 7 days in a 2-week cycle. Treatment was continued until disease progression. Of the 41 enrolled patients, 36 patients were evaluable with 61.1% disease control rate. The median progression-free survival and overall survival were 2.55 and 7.63 months, respectively. Regression change in tumor size stayed 10%-20% in five patients (13.9%) through 18 weeks after treatment, and two patients continued free from tumor progression at 30 and 42 weeks. Compared with moderate heavily pretreated mCRC patient subgroup (≤4 prior regimens), the severe heavily pretreated subgroup (≥5 prior regimens) showed similar disease control rate and survival benefit. Grade 3 or higher toxicities were documented only in 11 patients (26.8%). SL shows potential as a salvage regimen in refractory mCRC patients especially in the severe heavily pretreated setting and is well tolerated in these patients.